Over the past 7 years, several drugs have been found to have clinical activity against HIV, and a number of other agents are in various stages of pre-clinical and early clinical development. However, the long-term activity of all the available agents is limited by incomplete activity, long-term toxicity, and the development of viral resistance. We are presently exploring whether the use of combinations of anti-HIV agents may address some or all of these limitations of therapy. Combinations of anti- HIV drugs can reduce toxicity, capitalize on drug synergy, delay the development of resistance, target various cells in the body, and target various organs. We have previously studied the combinations of AZT and acyclovir, an alternating regimen of AZT and ddC, and a combination of AZT with acyclovir alternating with ddI alternating with ddC. We have more recently conducted a study comparing a regimen of AZT alternating with ddI with one of AZT given simultaneously with ddI in patients with AIDS or symptomatic HIV infection who have not been heavily pre-treated. The results indicate that the CD4 rises and increases in weight are greater and more sustained with the simultaneous regimen. In the near future, we are planning to test the combinations of (1) AZT plus - phosphonylmethoxyethyl)adenine (PMEA) and (2) AZT plus ddI plus neviripine.